Biomedical subjects

Christopher D Pack

Publications and source records attributed to Christopher D Pack.

4 recordsLinked to original sources

PubMed2005

Heat-shock protein 70 acts as an effective adjuvant in neonatal mice and confers protection against challenge with herpes simplex virus.

Immunization of the neonate is a highly desirable goal for vaccine developers, since the neonate is profoundly susceptible to a number of viral and bacterial pathogens. The neonatal immune system tends to generate Th2 recall responses, known as neonatal tolerance, which may not protect against viral challenge later in life. In this study we demonstrate that a potent immune proinflammatory stimulator, heat-shock protein 70 (hsp70), can act as an effective and safe adjuvant in neonates. Priming of neonates with hsp70 coupled to a viral MHC Class I-restricted epitope (gB498-505) and injection with recombinant gB generated strong cytotoxic T lymphocyte (CTL) responses and a Th1 primary T helper cell response during the neonatal period. In addition, enhanced CTL and predominant Th1 recall responses to viral antigens were observed following secondary challenge as adults. These responses were sufficient to allow protection against a lethal challenge with Herpes Simplex Virus Type-1 (HSV-1). Therefore, hsp70 in conjunction with viral epitopes and recombinant viral protein can perhaps prime protective immune responses to herpes viruses early in life when infection, which can be life-threatening, and the establishment of latency frequently occur.

Adjuvants, Immunologic↗

PubMed2004

Molecular adjuvants for mucosal immunity.

Mucosal surfaces represent the entry route of a multitude of viral pathogens. For many of these viruses, such as the herpes simplex viruses and human immunodeficiency virus, no effective vaccine exists. Hence, it is important that prospective vaccines engender maximal immunity at these susceptible sites. Genetic vaccines encoding adjuvant molecules represent one approach to optimize mucosal as well as systemic immunity. Promising candidates include various inflammatory cytokines and chemokines that might be used to enhance the primary response to a level sufficient for protection. Encouraging studies involving cytokines such as granulocyte/macrophage colony-stimulating factor, interleukin-2 (IL-2), IL-12, IL-18, and many others are examined. Notable chemokines that may offer hope in such efforts include IL-8, RANTES, CCL19, CCL21, and a few others. Combinatorial approaches utilizing several cytokines and chemokines will most likely yield the greatest success. In addition, as more is discovered regarding the requirements for memory development of T cells, boosters involving key cytokines such as IL-15 and IL-23 may prove beneficial to long-term maintenance of the memory pool. This review summarizes the progress in the use of genetic vaccines to achieve mucosal immunity and discusses the needed strategies to maximize long-term prospective immunity at this vulnerable entry site.

Adjuvants, Immunologic↗

PubMed2003

CD4+CD25+ T cells regulate virus-specific primary and memory CD8+ T cell responses.

Naturally occurring CD4+CD25+ regulatory T cells appear important to prevent activation of autoreactive T cells. This article demonstrates that the magnitude of a CD8+ T cell-mediated immune response to an acute viral infection is also subject to control by CD4+CD25+ T regulatory cells (Treg). Accordingly, if natural Treg were depleted with specific anti-CD25 antibody before infection with HSV, the resultant CD8+ T cell response to the immunodominant peptide SSIEFARL was significantly enhanced. This was shown by several in vitro measures of CD8+ T cell reactivity and by assays that directly determine CD8+ T cell function, such as proliferation and cytotoxicity in vivo. The enhanced responsiveness in CD25-depleted animals was between three- and fourfold with the effect evident both in the acute and memory phases of the immune response. Surprisingly, HSV infection resulted in enhanced Treg function with such cells able to suppress CD8+ T cell responses to both viral and unrelated antigens. Our results are discussed both in term of how viral infection might temporarily diminish immunity to other infectious agents and their application to vaccines. Thus, controlling suppressor effects at the time of vaccination could result in more effective immunity.

Adoptive Transfer↗

PubMed2003

Toll-like receptor ligand links innate and adaptive immune responses by the production of heat-shock proteins.

The report shows that CpG can exert additional adjuvant effects by inducing cells that are normally inferior antigen (Ag)-presenting cells to participate in immune induction by cross-priming. Macrophages (Mphi) exposed to protein Ag in the presence of bioactive CpG DNA released material that induced primary CD8(+) T cell responses in DC-naïve T cell cultures. This cross-priming event was accompanied by up-regulation of the stress protein response as well as inflammatory cytokine expression in treated Mphi. The material released was indicated to contain inducible heat shock protein-70 and epitope peptide, which in turn, were presented by dendritic cells (DCs) to responder T cells. Such an adjuvant effect by CpG may serve to salvage immunogenic material from otherwise inert depot cellular sites and additionally stimulate DCs to effectively cross-prime. The cross-priming, shown also to occur in vivo, may be particularly useful when Ag doses are low and have minimal opportunity for delivery to DCs for consequent direct priming.

Adjuvants, Immunologic↗